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Human cytochrome P-450 (CYP)2J2 is abundant in heart and active in biosynthesis of epoxyeicosatrienoic acids (EEls). Recently, we demonstrated that these eicosanoid products protect myocardium from ischemia-reperfusion injury. The present study utilized trans- genic (Tr) mice with cardiomyocyte-specific overexpression of human CYP2J2 to investigate protection toward toxicity resulting from acute (0, 5, or 15 mg/kg daily for 3 days, followed by 24-h recovery) or chronic (0, 1.5, or 3.0 mg/kg biweekly for 5 wk, followed by 2-wk recovery) doxorubicin (Dox) administration. Acute treatment resulted in marked elevations of serum lactate dehydrogenase and creatine kinase levels that were significantly greater in wild-type (WT) than CYP2J2 Tr mice. Acute treatment also resulted in less activation of stress response enzymes in CYP2J2 Tr mice (catalase 750% vs. 300% of baseline, caspase-3 235% vs. 165% of baseline in WT vs. CYP2J2 Tr mice). Moreover, CYP2J2 Tr hearts exhibited less Dox-induced cardiomyocytes apoptosis (measured by TUNEL) compared with WT hearts. After chronic treatment, comparable decreases in body weight were observed in WT and CYP2J2 Tr mice. However, cardiac function, assessed by measurement of fractional shortening with M-mode transthoracic echocardiography, was significantly higher in CYP2J2 Tr than WT hearts after chronic Dox treatment (WT 37 ± 2%, CYP2J2 Tr 47 ± 1%). WT mice also had larger increases in β-myosin heavy chain and cardiac ankryin repeat protein compared with CYP2J2 Tr mice. CYP2J2 Tr hearts had a significantly higher rate of Dox metabolism than WT hearts (2.2 ± 0.25 vs. 1.6 ± 0.50 ng·min-1·100 μg protein-1). In vitro data from H9c2 cells demonstrated that EEls attenuated Dox-induced mitochondrial damage. Together, these data suggest that cardiac-specific overexpression of CYP2J2 limited Dox-induced toxicity. [ABSTRACT FROM AUTHOR]

Background The subcommissural organ (SCO) differentiates early in ontogeny and remains fully active during the entire life span. It secretes glycoproteins into the cerebrospinal fluid (CSF) flowing through the Sylvius aqueduct (SA); these proteins either assemble to form Reissner fiber (RF), or remain soluble in the CSF and circulate throughout the CSF compartments. Overholser et al. (1954) have demonstrated that offspring littered by rats maintained on a diet deficient in folic acid and/or Vitamin B12 lack a SCO and develop hydrocephalus. This led them to propose that a dysfunction of the SCO during development leads to stenosis of the SA and hydrocephalus. We have investigated several animal models in which the SCO would play a role in the pathogenesis of hydrocephalus. We have now performed a comparative analysis of the changes occurring in the SCO-RF complex of these animal models, with the aim to find a landmark common to all hydrocephalic animals that might help to unfold the mechanism of SCO-dependant hydrocephalus. Materials and methods A comparative study of the SCO-RF complex and SA of five animal models characterized by a dysfunction of the SCO and development of hydrocephalus was carried out. Conventional light and electron microscopy and immunocytochemistry were applied. Results Model 1. Immunological blockage of RF formation by maternal transfer of antibodies against RF-glycoproteins: undamaged and secretory active SCO, missing RF, stenosed SA and moderate hydrocephalus. Model 2. hyh mice with a point mutation of aSNAP gene: undamaged and secretory active SCO, missing RF, obliterated SA and severe hydrocephalus. Model 3. HTx rat: subcommissural portion (two distal thirds) of SCO missing, supracommissural portion (rostral third) of SCO secretory active, RF absent, obliterated SA and severe hydrocephalus. Model 4. Transgenic mice deficient in transcription factor RFX4- v3: subcommissural portion of SCO missing, supracommissural portion of SCO secretory active, RF absent, patent SA and moderate to severe hydrocephalus. Model 5. fyn knockout mice: subcommissural portion of SCO missing, supracommissural portion of SCO secretory active, RF absent, SA with an abnormal shape and severe hydrocephalus. Conclusion 1. The SCO is formed by two zones: the subcommissural and the supracommissural portions. 2. Differentiation of both zones would be controlled by different genes. 3. The subcommissural portion of the SCO is essential for RF formation. Mutant and transgenic animals lacking this portion, although still have a secretory active flow of CSF throughout SA. 6. Absence of RF could cause SA obliteration or a turbulent CSF flow through SA what, in turn, would lead to hydrocephalus. Supported by Fondecyt 1030265 (Chile), the Intramural Program of the NIH, NIEHS (USA), and MEXT (Japan). [ABSTRACT FROM AUTHOR]